Ruxolitinib Phosphate, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

PRIMARY OBJECTIVES:

I. Determine whether treatment with ruxolitinib in combination with conventional neoadjuvant
and post-surgical chemotherapy is safe and tolerable in the primary therapy for epithelial
ovarian, fallopian tube, or primary peritoneal carcinoma. (Phase I) II. Demonstrate whether
treatment with ruxolitinib in combination with conventional neoadjuvant and post-surgical
chemotherapy results in a prolonged progression-free survival when compared to chemotherapy
alone, in primary therapy for epithelial ovarian, fallopian tube, or primary peritoneal
carcinoma. (Phase II)

SECONDARY OBJECTIVES:

I. Determine frequency of patients who do not receive surgery within 6 weeks of completing
cycle 3 therapy for reasons other than non-response, disease progression, or medical
contraindications. (Phase I) II. Determine if continuation of ruxolitinib as maintenance
therapy in participants who complete 6 cycles of standard chemotherapy in combination with
ruxolitinib and have not experienced unacceptable toxicity or disease progression is safe and
tolerable. (Phase I) III. Determine the impact of ruxolitinib in combination with
chemotherapy on progression-free survival as a function of proposed exploratory biomarkers -
ALDH+ CD133+ (possibly also CD24+ CK19+) co-staining by AQUA immunofluorescence (IF); ratio
of tumor expression of CD8:FOXP3 by immunohistochemistry (IHC); and tumor CD3, CD4, TAI-1,
HLA class I and II, CD68 expression by IHC in archived tumor tissue and serum C-reactive
protein (CRP) and IL-6 levels in pre-treatment serum. (Phase II) IV. Investigate the
prognostic significance of exploratory laboratory parameters in terms of both
progression-free survival and overall survival in women receiving conventional chemotherapy
alone. (Phase II) V. Determine whether treatment with ruxolitinib in combination with
conventional chemotherapy is associated with total gross resection rate at time of interval
cytoreductive surgery. (Phase II) VI. Determine whether treatment with ruxolitinib in
combination with conventional chemotherapy is associated with complete pathologic response
defined at interval cytoreductive surgery. (Phase II) VII. Demonstrate whether treatment with
ruxolitinib in combination with conventional chemotherapy results in an improvement in
overall survival in primary management of epithelial ovarian, fallopian tube, or primary
peritoneal carcinoma. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of ruxolitinib phosphate, followed by a
phase II study.

PHASE I PORTION OF STUDY IS COMPLETE (04/06/2018)

PHASE I (COURSES 1-3): Patients receive ruxolitinib phosphate orally (PO) twice daily (BID)
on days 1-21, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, and carboplatin
IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of
disease progression or unacceptable toxicity. Within 6 weeks after completion of course 3,
patients undergo tumor reductive surgery (TRS).

PHASE I (COURSES 4-6): Within 6 weeks of TRS, patients receive ruxolitinib phosphate PO BID
on days 1-21, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30
minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease
progression or unacceptable toxicity. If TRS is not performed due to non-response or medical
contraindications and criteria for discontinuation of protocol therapy have not been met,
patients should resume ruxolitinib phosphate, paclitaxel, and carboplatin within 6 weeks of
completing course 3 of therapy.

MAINTENANCE THERAPY: Within 3 weeks after completion of course 6, patients receive
ruxolitinib phosphate PO BID. Treatment continues in the absence of disease progression or
unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I (COURSES 1-3): Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and
carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 courses in the
absence of disease progression or unacceptable toxicity. Patients then undergo TRS.

ARM I (COURSES 4-6): Within 4 weeks of surgery (within 6 weeks of completion of course 3 in
patients who do not undergo TRS), patients receive paclitaxel IV over 1 hour on days 1, 8,
and 15 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3
courses in the absence of disease progression or unacceptable toxicity.

ARM II (COURSES 1-3): Patients receive ruxolitinib phosphate PO BID on days 1-21 and
paclitaxel and carboplatin as in arm I. Treatment repeats every 21 days for 3 courses in the
absence of disease progression or unacceptable toxicity. Patients then undergo TRS.

ARM II (COURSES 4-6): Within 4 weeks of surgery (within 6 weeks of completion of course 3 in
patients who do not undergo TRS), patients receive ruxolitinib phosphate PO BID on days 1-21
and paclitaxel and carboplatin as in arm I. Treatment repeats every 21 days for 3 courses in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients in phase I are followed up until resolution of
adverse events, and patients in phase II are followed up every 3 months for 2 years and then
every 6 months for 3 years.

Inclusion Criteria:

- Patients must have clinically and radiographically suspected and previously untreated
International Federation of Gynecologic and Obstetrics (FIGO) stage III or IV
epithelial ovarian, primary peritoneal or fallopian tube cancer, high grade, for whom
the plan of management will include neoadjuvant chemotherapy (NACT) with interval
tumor reductive surgery (TRS) who have undergone biopsies for histologic confirmation

- Institutional confirmation of Mullerian epithelial adenocarcinoma on core biopsy (not
cytology or fine needle aspiration) or laparoscopic biopsy; (for phase II of the study
formalin-fixed paraffin-embedded [FFPE] tissue should be available for laboratory
analysis); patients with the following histologic epithelial cell types are eligible:
high grade serous carcinoma, high grade endometrioid carcinoma, clear cell carcinoma,
or a combination of these

- All patients must have measurable disease as defined by Response Evaluation Criteria
In Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one lesion
that can be accurately measured in at least one dimension (longest diameter to be
recorded); each lesion must be >= 10 mm when measured by computed tomography (CT),
magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm
when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured
by CT or MRI

- Appropriate stage for study entry based on the following diagnostic workup:

- History/physical examination within 28 days prior to registration

- Radiographic imaging of the chest, abdomen and pelvis within 28 days prior to
registration documenting disease consistent with FIGO stage III or IV disease

- Further protocol-specific assessments

- Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status of 0, 1, or 2
within 28 days prior to registration

- Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl; this ANC cannot
have been induced by granulocyte colony stimulating factors (within 14 days prior to
registration)

- Platelets greater than or equal to 100,000/mcl (within 14 days prior to registration)

- Hemoglobin greater than 9.0 mg/dl (transfusions are permitted to achieve baseline
hemoglobin level) (within 14 days prior to registration)

- Estimated creatinine clearance (CrCl) >= 50 mL/min/1.73 m^2 according to the
Cockcroft-Gault formula (within 14 days prior to registration)

- Bilirubin =< 1.5 x upper limit of normal (ULN) (within 14 days prior to registration)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (within
14 days prior to registration)

- Alkaline phosphatase =< 2.5 x ULN (within 14 days prior to registration)

- Neurologic function: neuropathy (sensory and motor) less than or equal to Common
Terminology Criteria for Adverse Events (CTCAE) grade 1

- Ability to swallow and retain oral medication

- The patient must provide study-specific informed consent prior to study entry

Exclusion Criteria:

- Patients with suspected non-gynecologic malignancy, such as gastrointestinal

- Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer and other specific malignancies are excluded if there is any
evidence of other malignancy being present within the last three years (2 years for
breast cancer); patients are also excluded if their previous cancer treatment
contraindicates this protocol therapy

- Patients who have received prior chemotherapy for any abdominal or pelvic tumor within
the last three years are excluded; patients may have received prior adjuvant
chemotherapy and radiotherapy for localized breast cancer, provided that it was
completed more than 2 years prior to registration, the patient remains free of
recurrent or metastatic disease and hormonal therapy has been discontinued

- Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis or thoracic cavity within the last three years are excluded; prior radiation
for localized cancer of the head and neck or skin is permitted, provided that it was
completed more than three years prior to registration, and the patient remains free of
recurrent or metastatic disease

- Patients who have received any targeted therapy (including but not limited to
vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management
of their epithelial ovarian, fallopian tube or peritoneal primary cancer

- Patients with mucinous carcinoma, low grade endometrioid carcinoma, low grade serous
carcinoma or carcinosarcoma

- Patients with synchronous primary endometrial cancer, or a past history of primary
endometrial cancer, unless all of the following conditions are met: stage not greater
than I-A, grade 1 or 2, no more than superficial myometrial invasion, without vascular
or lymphatic invasion; no poorly differentiated subtypes, including serous, clear cell
or other FIGO grade 3 lesions

- Severe, active co-morbidity defined as follows:

- Chronic or current active infectious disease requiring systemic antibiotics,
antifungal or antiviral treatment

- Known brain or central nervous system metastases or history of uncontrolled
seizures

- Clinically significant cardiac disease including unstable angina, acute
myocardial infarction within 6 months from enrollment, New York Heart Association
class III or IV congestive heart failure, and serious arrhythmia requiring
medication (this does not include asymptomatic atrial fibrillation with
controlled ventricular rate)

- Partial or complete gastrointestinal obstruction

- Patients who are not candidates for major abdominal surgery due to known medical
comorbidities

- Patients with any condition that in the judgment of the investigator would jeopardize
safety or patient compliance with the protocol

- Patients who are unwilling to be transfused with blood components

- Concurrent anticancer therapy (e.g. chemotherapy, radiation therapy, biologic therapy,
immunotherapy, hormonal therapy, investigational therapy)

- Receipt of an investigational study drug for any indication within 30 days or 5
half-lives (whichever is longer) prior to day 1 of protocol therapy

- Patients who, in the opinion of the investigator, are unable or unlikely to comply
with the dosing schedule and study evaluations

- Patients who are pregnant or nursing; women of child-bearing potential (WOCBP) must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation; WOCBP
must have a screening negative serum or urine pregnancy test within 14 days of
registration; a second pregnancy test must be done within 24 hours prior to the start
of the first cycle of study treatment; women must not be breastfeeding

- Women who are not of childbearing potential (i.e., who are postmenopausal or
surgically sterile) do not require contraception

- Women of childbearing potential (WOCBP) is defined as any female who has
experienced menarche and who has not undergone surgical sterilization
(hysterectomy and/or bilateral oophorectomy) or who is not postmenopausal;
menopause is defined clinically as 12 month amenorrhea in a woman over 45 in the
absence of other biological or physiological causes; in addition, women under the
age of 55 must have a documented serum follicle stimulating hormone (FSH) level
greater than 40mIU/mL

- Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
infection or known history of tuberculosis